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Fragment screening of inhibitors for MIF tautomerase reveals a cryptic surface binding site

Fragment screening by in silico docking followed by X-ray crystallography demonstrates the formation of a previously unreported surface binding site in MIF that is hydrophobic and surrounded by aromatic side-chain residues. In the course of a fragment screening campaign by in silico docking followed...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (6), p.1821-1824
Main Authors: McLean, Larry R., Zhang, Ying, Li, Hua, Choi, Yong-Mi, Han, Zuoning, Vaz, Roy J., Li, Yi
Format: Article
Language:English
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Summary:Fragment screening by in silico docking followed by X-ray crystallography demonstrates the formation of a previously unreported surface binding site in MIF that is hydrophobic and surrounded by aromatic side-chain residues. In the course of a fragment screening campaign by in silico docking followed by X-ray crystallography, a novel binding site for migration inhibitory factor (MIF) inhibitors was demonstrated. The site is formed by rotation of the side-chain of Tyr-36 to reveal a surface binding site in MIF that is hydrophobic and surrounded by aromatic side-chain residues. The crystal structures of two small inhibitors that bind to this site and of a quinolinone inhibitor, that spans the canonical deep pocket near Pro-1 and the new surface binding site, have been solved. These results suggest new opportunities for structure-based design of MIF inhibitors.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.02.009